Malaria vaccines containing T and B cell epitopes of the Plasmodium falciparum circumsporozoite (CS) protein are being developed in an effort to block establishment of the pre-erythrocytic parasite stages and prevent the 200-300 million infections that occur world-wide. Phase I studies (carried out by the PI) of synthetic peptide vaccines indicate that the immune response to P. falciparum CS protein is both positively and negatively regulated by class II associated immune mechanisms. Due to their limited complexity, synthetic peptide vaccines provide unique immunogens for dissecting the genetic and cellular mechanisms that function in regulation of vaccine-induced responses. Antigen specific responses elicited by vaccines, as welt as by infectious pathogens, are initiated when dendritic cells (DC) of the innate immune system presenting capacity of DC can affect the differentiation of naive CD4+ T ceils into T helper (Th) cells that enhance humoral and cellular immunity, or CD4+ T regulatory (Tr) ceils that downregulate immune responses. Specific Aim 1 will focus on the initial cellular interactions between the innate and adaptive immune responses that are important for CS-specific CD4 T helper responses. DC from human volunteers and inbred strains of mice will be examined to determine DC from R and NR and also to examine the effect of vaccine configuration/adjuvant formulations overcome hypo-responsiveness by modulating DC function. Specific Aim 2 will examine whether CD4+ Tr cells that downregulate antibody and CD4+ T helper cells are present in non-responders to CS peptide vaccines. Specific Aim 3 will investigate protective efficacy of P. falciparum vaccine induced antibody and cellular responses using transgenic P. berghei sporozoites genetically modified to express P. falciparum CS repeats (PfPb). The availability of this unique hybrid PfPb sporozoite/murine model will facilitate (1) pre-clinical screening of humoral and cellular immunity elicited by P. falciparum vaccines and (2) evaluation of anti-P, falciparum repeat immune responses elicited in human volunteers immunized with malaria vaccines.